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Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONREFERENCES |
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KEY WORDS: • esophageal cancer • antioxidants
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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). On the basis of
these results and other information, a joint U.S.-China nutritional
intervention study on this disease was launched in the early 1980s with
the participation of many investigators from the Cancer Institute of
the Chinese Academy of Medical Sciences and the U.S. National Cancer
Institute. A large-scale intervention study involving 29,584
subjects in an eight-group design was conducted from 1995 to 1991
to test the effects of the following four combinations of nutrients:
1) retinol and zinc; 2) riboflavin and niacin;
3) vitamin C and molybdenum; and 4) vitamin E,
ß-carotene and selenium. The nutrients were given in tablets, which
were taken daily. The doses ranged from one to two times the U.S.
Recommended Dietary Allowance (RDA) values. The highlight of the
results was that supplementation with Group 4 nutrients significantly
decreased mortality rate from stomach cancer, due primarily to the
decrease in deaths resulting from adenocarcinomas of the gastric cardia
(Blot et al. 1993
). Group 4 nutrients also lowered the
total mortality rate and showed signs of other beneficial effects.
These results suggest the possible role of antioxidant nutrients in
protection against adenocarcinomas of the gastric cardia or
gastroesophageal junction in a population that has a low intake of
these nutrients.
I also had the opportunity to work on nutrition and gastric cancer in a
high incidence area of Linqu of the Shangdong province in northern
China. Previous epidemiologic studies indicated that the possible risk
factors include high intake of salt, salty food, fermented sour
pancakes and cigarette smoking, whereas, consumption of fresh
vegetables and fruits are protective factors. In collaboration with
Drs. Lian Zheng and Wei-Cheng You of the Beijing Institute for
Cancer Research and Dr. William Blot of the U.S. National Institutes of
Health, we analyzed the serum levels of micronutrients. Serum
concentrations of vitamin C and ß-carotene were significantly lower
among individuals with intestinal metaplasia (a precancerous state)
than in those with less severe lesions such as chronic atrophic
gastritis or superficial gastritis (Zhang et al. 1994
).
On the basis of these and other results, an intervention trial with
vitamins C and E and selenium (combined) has been initiated and is
ongoing in Linqu. The other arms of this study are antibiotics for the
eradication of Helicobacter pylori, which is suspected as a
risk factor, and a garlic preparation. Garlic consumption has been
found previously to be associated with lower gastric cancer risk in
this area.
To understand the mechanisms for the pathogenesis of adenocarcinoma at
the gastroesophageal junction, we used a esophagoduodenal anastomosis
(EDA) model with rats. In this model, the distal esophagus is
transected proximally to the gastroesophageal junction and anastomosed
to the duodenum. This surgical procedure causes reflux of
gastroduodenal contents into the esophagus. With time, columnar cells
begin to replace the squamous cells of the distal esophageal
epithelium, a situation known as columnar-lined esophagus (CLE) or
Barrett’s esophagus; subsequently, adenocarcinomas will develop but at
a low rate. In some studies, N'-nitrosonornicotine was used
to enhance tumor formation. We noticed that the EDA rats were anemic
because of the loss of gastric functions. In a subsequent experiment,
we supplemented the rats with iron dextran, which prevented anemia. To
our surprise, adenocarcinomas occurred at a high rate and
N'-nitrosonornicotine was no longer needed to enhance
carcinogenesis (Goldstein et al. 1997
). Subsequent
studies suggest that the inflammation caused oxidative damage to the
cells (which is enhanced by iron supplementation) and is the major
driving force for carcinogenesis (Chen et al. 1999
,
Goldstein et al. 1998
). If this is true, it would be
interesting to determine whether the formation of adenocarcinoma could
be inhibited by dietary supplementation with vitamin E and selenium in
a situation mimicking our previous human intervention study in Linxian.
The vitamin E and selenium supplementation experiment (10 times the
normal levels of the AIN93M diet in 
-tocopherol acetate and/or
sodium selenate), indicated that vitamin E supplementation inhibited
adenocarcinoma formation, especially in the selenium-supplemented
group. However, selenium supplementation enhanced carcinogenesis. This
may be due to the chemical form or dose of selenium used in the
experiment.
Additional studies will be conducted with a newly developed model known
as esophagogastroduodenal anastomosis (EGDA) (Chen et al. 1999
). This
procedure produces adenocarcinomas without compromising the nutritional
status of the rats and thus is more suitable for testing our hypothesis
on oxidative stress-induced carcinogenesis and its possible
prevention by antioxidant nutrients. Such studies are expected to shed
light on the etiology and prevention of gastroesophageal cancers in
humans.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONREFERENCES |
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1.
Blot W. J., Li J.-Y., Taylor P. R., Guo W., Dawsey S., Wang G.-Q., Yang C. S., Zheng S.-F., Gail M., Li G.-Y., Yu Y., Liu B.-Q., Tangrea J., Sun Y.-H., Liu F., Fraumeni J. F., Jr, Zhang Y.-H., Li B. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl. Cancer Inst. 1993;85:1483-1491
2.
Chen X., Yang G.-Y., Ding W. Y., Bondoc F., Curtis S. K., Yang C. S. An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload. Carcinogenesis 1999;20:1801-1808
3.
Goldstein S. R., Yang G.-Y., Chen X., Curtis S. K., Yang C. S. Studies of iron deposits, inducible nitric oxide synthase and nitrotyrosine in a rat model for esophageal adenocarcinoma. Carcinogenesis 1998;19:1445-1449
4.
Goldstein S. R., Yang G.-Y., Curtis S. K., Reuhl K. R., Liu B.-C., Mirvish S. S., Newmark H. L., Yang C. S. Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen. Carcinogenesis 1997;18:2265-2270
5. Yang C. S., Miao J., Yang W., Huang M., Wang T., Xue H., You S., Lu J., Wu J. Diet and vitamin nutrition of the high esophageal cancer risk population in Linxian, China. Nutr. Cancer 1982;4:154-164[Medline]
6. Zhang L., Blot W. J., You W.-Y., Chang Y.-S., Liu X.-Q., Kneller R. W., Zhao L., Liu W.-D., Li J.-Y., Jin M.-L., Xu G.-W., Fraumeni J. F., Jr, Yang C. S. Serum micronutrients in relation to precancerous gastric lesions. Int. J. Cancer 1994;56:650-654[Medline]
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